Blepharitis is one of the most frequent reasons for ophthalmologic consultation. This condition has been linked to the presence of the mite Demodex folliculorum. In the vast majority of cases, this is an ectoparasite guest in humans without causing harm. However, in some individuals, especially those with compromised immune systems, or diseases such as rosacea, Demodex population can increase dramatically, resulting in a condition known as demodicosis. At present there are a variety of pharmaceuticals for treating demodicosis, which must be monitored carefully because of the risk of toxicity. Others have limited effectiveness because the mite develops resistance.
Demodex folliculorum is a mite that typically resides in the hair follicle, which causes chronic eczematous blepharitis (Ibis Sedeño, Ester Novoa, Vivivan Register, Francisco Garcia and Raul San Martin Salem DA-B, the-shazly A Nabih N, El-Bayoumy Y, Saleh S., Blepharitis by Demodex infestation, diagnosis and treatment. Revista Cubana Oftalmol 2006. 19). It has also been associated with other diseases such as rosacea, folliculitis, perioral dermatitis among others (Forton F, Seys B. Density of Demodex infestation in rosacea: a case control study using standardized skin surface biopsy, British J Dermatol 1993; 128: 650-59). However, the role of Demodex as a causative agent of human disease is still a matter of controversy. These mites are acquired shortly after birth and normalize skin wildlife. Their number is increased in proportion to the available food supply, so that they increase during puberty when the sebaceous glands proliferate. It is very common to find in inflammatory facial lesions, but causality is difficult to prove (Elston D M Demodex mites: Facts and Controversies Clinics in Dermatology September 2010; 28 (5): 502-4).
Demodex also in addition to man affects a variety of animals such as dog, cat, horse, cow, pig, goat, bat, rat, mouse, rabbit and hamster but differences were found in the Demodex species of different animals, e.g. it has been called Demodex canis in dogs and Demodex phyilloides in pigs (Corridor R, Nava, Tovilla J, Munoz S., Blepharitis Demodex folliculorum Rev Fac Med UNAM 43 (4):125-9).
Blepharitis association with the presence of Demodex infestation is probably more common than suspected by ophthalmologists. This parasitic mite prefers to reside in hair follicles, sebaceous glands and the eyelashes of man. It is widely distributed worldwide. We have found two types: Demodex longus infestation longus and Demodex brevis infestation.
The Demodex longus infestation and Demodex brevis infestation are found in about 10% of biopsies of healthy skin, where they are present in about 12% of all hair follicles. Both species are most common on the face. Demodex brevis is the predominant mite having a wider distribution in the body. Normal colonization rates are between 20% and 80%. Men often are more affected than women, probably because they have more sebaceous glands, although the opposite was found among Australian Aborigines (Norn M S Demodex infestation Incidence and possible pathogenic role in the human eyelid. Chapter IV: Incidence in the ocular region of a clinical material Acta Ophthalmol, Demodex infestation Suppl 1970; 108: . . . 43-52).
A study of cases and controls assessed the prevalence of infection by Demodex infestation in one hundred patients with chronic blepharitis and 100 healthy controls. The prevalence in the group of blepharitis, was 63% compared with the control group only having mites in 33.33% of cases (p<0.001). The analysis adjusted for gender showed that women had the mite in 44.63% and men in 53.85% of cases proving that Demodex infestation plays an important role in the pathophysiology of chronic blepharitis (Gamboa J, Cortes M, A. Rodriguez, Incidence of Demodex infestation in blepharitis Rev Mex Ophthalmol 2003; 77 (2): 44-7).
A meta-analysis with a solid and comprehensive design was conducted and reviewed the available literature on the association of Demodex infestation with blepharitis including eleven articles covering reports from four different countries and 4,741 patients participating (2,098 blepharitis and 2,643 controls. The analysis found a pooled OR of 4.89 with a confidence interval of 95%, 3.00 to 7.97).
Sensitivity analysis showed that the pooled results effects in different models, language, sample size and control groups were completely consistent, demonstrating a stable association between Demodex infestation and blepharitis. The authors conclude that when the conventional treatment of blepharitis fails, one should evaluate the possibility of Demodex infestation and consider the respective acaricide treatment (Zhao Y E, LP Wu, Hu L, Xu J R Association of blepharitis With Demodex, Meta-analysis, Ophthalmic Epidemiol., April 2012; 19 (2): 95-102).
Demodicosis is the term used to describe skin diseases caused by mites of the genus Demodex folliculorum longus and Demodex brevis. They live as normal microflora in the skin of humans especially in the hair follicle and pilosebaceous complex. This mite was discovered in 1841 in the external auditory meatus. Subsequently, it was described in detail by Simon in 1842, who proposed the term Demodex infestation, and D. folliculorum, D. Fulocularum and D. brevis (Owen R, 1843—A list of the parasitic Protozoa, Helminths and arthropods recorded from species of the Family Anatidae).
Demodex sp are man bound ectoparasites. More frequently they inhabit in high density areas of craniofacial skin, including nose and peri orbital region. It is known that 10% of all biopsies and 12% of all hair follicles present with the human Demodex mites. The prevalence of both species increases with age, but the prevalence of Demodex brevis is lower. Both species are found in facial demodicosis, which is the site of infection (Norn M S, 1972) were it occurs most often. In the rest of the body, Demodex brevis has a broader distribution, causing body demodecosis (Norn M S Demodex infestation Incidence and possible pathogenic role in the human, Acta Ophthalmologica Suppl eyelid 1970; 108: 1-85).
Infection by Demodex Spp produces in humans keratoconjunctivitis and blepharitis (AE Rodriguez, 2005). It has also been associated with other dermatoses such as rosacea and peri oral dermatitis. Recently, evidence has been found of an association with basal cell carcinoma (Amichai B, 1992; Forton F, 1993; Erbagci Z, Robinson T W E 2003—Demodex infestation and Rosacea Arch Dermatol 1965; 92: 542-544).
The biology of Demodex folliculorum infestation biology comes from the Greek demos meaning fat; and dex, meaning woodworm (Forton F., 1993). Demodex belongs to the arthropod phylum, class Arachnida, order: Acari; superfamily: Demodicodoidea. Based on taxonomic criteria, Martinez-Baez M (1953) it is classified as a species that affect humans, such as Demodex longus infestation and Demodex brevis (Markell E K, John D T, Krotoski W A Arthropods and Human Disease In. WB Saunders Company, editors. Markell and Voge's Medical Parasitology. Philadelphia, 1999, p. 361.).
The life cycle of Demodex folliculorum infestation occurs in the opening of the hair follicle host. The female makes its way into the sebaceous gland into which it lays eggs about 12 hours, the larvae then hatches 60 hours after ovoposition. The larvae is fed and continuously moving and after a life of approximately 40 hours, gives rise to the protonymph. This occurs in the pilosebaceous duct. The protonymph eats continuously and is simultaneously transported to the follicle opening in the pilosebaceus duct. The legs of the protonymph compared to the adult are weakly developed, for this reason offers little resistance. The protonymph after a 72 hour life gives rise to deutonymph. After a short time interval during which the deutonymph inches towards the skin surface, it can be in a period after 36 hours, but usually remains about 12 hours and probably only in the dark or partial light. The deutonymph then enters the follicle and after a life of 60 hours moves on to become an adult. The female remains in the mouth of the follicle until the time of copulation. Adult female moves from inside the mouth of the follicle, after oviposition, where after a life of approximately 120 hours they die (Desch C E, 1977).
It has been shown that about half of the mites at the mouth of the follicle are dead. Dead mites tend to block the follicular opening, which would tend to reduce the opportunity for new infestations of individual follicles. A rough estimate of the evolutionary cycle of the female would be: 60 hours egg, larva 36 hours, protonymph 72 hours, 60 hours deutonymph, adult female 120 hours for a total of 348 hours or 14 and a half days. This has been evidenced in vitro culture (Acaricide Blepharitis by Demodex folliculorum Biomicroscopic findings, Arch Ophthalmol Soc Españ 1993; 65: 455-462).
It has been experimentally shown that Demodex at all stages flees the light (negative phototaxis). Larva, and adult female protonymph migrate into the wider portion of the follicle, while the adult male and deutonymph can move towards the narrower part thereof. The deutonymph is more resistant to heat and desiccation at the other stages (Humiczewska M., Demodex folliculorum and Demodex brevis Acarides as the factors of marginal chronic blepharitis, Wiad Parazytol 1991; 37 (1): 127-30).
Regarding habitat, although the Demodex longus infestation and Demodex brevis have been found in the skin pilosebaceus complex, they occupy different sites. Demodex longus infestation level inhabits the sebaceous glands or pilosebaceous ducts (Forton F et al. 1993 and Duke-Elder S 1974). Meanwhile, Demodex brevis inhabits sebaceous and meibomian glands. Demodex longus infestation consumes cells of the follicular epithelium, however epithelial metaplasia and follicular distension can occur only if there are 6 or more mites present in the same follicle, therefore it is considered a low grade pathogen.
Demodex brevis apparently consumes sebaceous glands, but there is no evidence of metaplasia (Uyttebroeck W, Nijs I, Maudgal P C, Missotten L., Incidence of Demodex folliculorum on the eyelash follicle in normal people and in blepharitis patients, Bull. Soc. Belge. Ophtalmol, 1982; 83-7).
Demodex has been implicated as the agent associated with persistent dry skin, erythematous scaly rosacea resembling pityriasis, the papulopustular or the granulomatous rosacea (Amichai B, 1992), including location in isolated inflammatory papules, alopecic scalp and in some cases blepharitis, seborrhea, skin atrophy, palpebral skin pigmentation, and meibomitis chalazia. It has also been associated in immunosuppressed patients with leukemia or HIV infection and cancer chemotherapy (liva J, 2010—Morras P G, Santos S P, Imedio I L, Echeverria M L, Hermosa J M., Rosacea-like Demodicidosis in an immunocompromised child Pediatr Dermatol., 2003; 20: 28-30).
Demodex brevis is a more solitary species than Demodex folliculorum longus. Usually a single mite lives or at most two, presumably a female. (Desch C E., 1972). Usually a single species is found although the two species together may also be found. It has been shown that the most common place is on the nose, then the external auditory meatus and eyelashes (Duke-Elder S. 1974), and it can also be found on the cheek. Demodex is more abundant in the lower eyelid than at the top, which can be explained by the shortest migration path from the nose. The severity of the infection may play a role in migration to the eyelashes, and searching for other niches where they can play and have enough food (Norn M S Incidence of Demodex infestation on skin of lids and donot ophthalmologica Act 1982; 60: 575-583).
In related studies, it was found that an adult Demodex walks about 7 to 8 mm in 30 minutes. Duke-Elder and Dubois (1974) found no mites in children under 5 years, but did find mites in 50% of children aged between 5 and 10 years and universally in individuals aged over 25 years old (Coston 1987). Norn M S (1982) found mites in virtually all middle-aged subjects (7 years). Post and Juhlin E (1965), found 59% prevalence by Demodex species. Madeira and Sogava (1993) reported 72% of patients infected by Demodex, of which 51% have Demodex folliculorum longus infestation, 2% Demodex brevis and 19% both species.
Aylesworth R & Vance J C (1982) studied these mites in a consecutive series of skin biopsies submitted to a Dermatopathology laboratory, finding that 12% of all follicles contain Demodex mites. The prevalence of both species increases with age, but the prevalence of Demodex brevis was always lower. Although the face skin is more heavily infested by both species, Demodex brevis has a wider distribution in the body. Men are infected more than women with both species.
Meral Turk et al. (2007) noted that the incidence of Demodex folliculorum infestation was higher in patients with blepharitis compared to normal controls. Comparative studies of demodicosis in humans and other mammals indicate that keratinization, hyperplasia, bloating, and aggregation of melanocytes can be even wider if populations of Demodex folliculorum infestation accumulate in the follicles of the eyelids. Large populations of Demodex brevis can destroy the glandular cells, producing granuloma on the eyelid and plug conduits or meibomian sebaceous glands. Further studies may implicate one or both species with microorganisms, transfer agents or synergists, or both, in the production of ocular disease in man (Madeira N G, Sogava M I. Prevalence of Demodex folliculorum infestation and Demodex brevis A sample of the population of Botucatu, Sao Paolo Trop. Med. Rev. Bras. Soc., 1993; 26 (4): 221-224).
Ayres S (1967) and Georgala S (2001), assessed the significance of Demodex folliculorum longus infestation in the etiology and course of rosacea, concluding that although Demodex mites do not appear to be the cause of rosacea, they can represent an important cofactor especially in papula-pustular rosacea. Immunohistochemical findings suggest that a delayed hypersensitivity reaction, possibly triggered by antigens of follicular origin, probably related to Demodex longus infestation, can occur, encouraging the progression of the condition to papulopustular stage. Recently results of the presence of Bacillus oleronius in Demodex mites within a patient papule-pustular rosacea were published. It was found that this bacterium produces antigens capable of stimulating proliferation of mononuclear cells in peripheral blood in 73% of rosacea patients compared with control subjects (p=0.0105). In addition, a pool of sera from 6 patients with papule pustular rosacea identified two proinflammatory proteins of 62 kDa and 83 kDa-produced by this bacterium (N Lacey et al., 2007). Further studies revealed the existence of a statistically significant correlation between serum immunoreactivity antigens Bacillus oleronius, Demodex sp., and facial rosacea. A total of 59 registered patients prospectively and consecutively, a significant positive correlation between serum immunoreactivity with facial rosacea (p=0.009) and ocular Demodex infection (p=0.048) was found. Facial rosacea patients had significantly higher Demodex infection compared to those without rosacea (p=0.014) (Jianjing L i, 2010). Although it is still speculative, existence of a causal relationship between serum immunoreactivity, ocular infection by Demodex and rosacea, there is speculation of a new paradigm that links pathogens such as Demodex and microbial infection by B. Oleronius with inflammation on the ocular surface. The co-morbidity of both microorganism Demodex mites and B. Oleronius is based on symbiosis of the latter in the mite (Kuhnigk T. 1995; Jianjing L i, 2010—Robinson T W E Demodex infestation and Rosacea Arch. Dermatol 1965; 92: 542-544.).
Treatment of Demodicidosis is currently aimed at eliminating the parasite. One of the traditional methods is to expose the tails of the mites outside the hair follicle, by cleaning palpable borders and edges with ether, followed by observation of the mites with a slit lamp and then application of selenium disulphide 0.5% alone or in combination with hydrocortisone acetate 0.5% based petrolatum or benzyl benzoate (runner-Osorio, 2000; Norn M S, 1982). There is also used as treatments ointments based on ammoniated mercury (1 to 3%) and yellow mercuric oxide, although this treatment has limited duration of six weeks under common control, due to the corneal toxicity of mercury. Other treatments include antimicrobial topical metronidazole 2%, permethrin 1%, lindane 1%, crotamiton 10% (Forton F, 1993; Junk A K, 1998) and erythromycin, however it is now known that the mites have developed resistance to these treatments. Alcohol is also used at 10% concentration, povidone-iodine and also the use of Ivermetrin (Aquilina C, 2002).
Other treatments include the use of essential oils. In vitro studies have shown that the essential oil extracted from Tea Tree, has the property of rapidly eliminating the Demodex mite (messager S, 2005; Gao Y Y, 2005). The tea tree oil is extracted from the leaves of the tree Melalua alternifolia (Myrtaceae), which is native to eastern Australia. The oil showed acaricidal activity against Demodex in a short time of 4 minutes, but has the disadvantage of being toxic. In a recent study, in vivo use of Tea tree oil as a 50% solution with fixed oil of the Macadamia nut ternifolia (Proteaceae), as a treatment to eliminate Demodex mites living in the flanges of the patients reported afflicted with ocular rosacea, demonstrated improved conjunctival irritation and inflammation at six weeks of treatment (Y Y Gao, 2005; Gao Y Y, 2007).
Wen-ge Li (2005) showed acaricidal activity against Demodex with five creams made from volatile oils of Curcuma longa (Zingiberaceae), Syzygium aromaticum (Myrtaceae), Eucalyptus globulus (Myrtaceae), Zingiber coralliaum (Zingiberaceae) and Litsea pungens Hemsl (Laureceae); finding a maximum acaricidal activity with a cream made with oil Curcuma longa. Subsequently, Zhao Yae et al (2006) demonstrated the effectiveness of eucalyptus tree oil against Demodex infestation. Song Bo et al (2010), evaluated the effect in vitro of the acaricide Gengibre pure blue (Zingiberaceae) essential oil, finding that this was able to eliminate Demodex folliculorum mites in 14.42-1.14 minutes of treatment and, Demodex brevis in 8.3 to 0.86 minutes of treatment. All these products have an irritant and toxic long-term effect.
At present there are a variety of pharmaceuticals for treating demodecosis, which must be used carefully because of the risk of toxicity. Others have limited effectiveness because the mite develops resistance.
The mite Demodex folliculorum, was discovered by Henle and Berguer in 1841 and described in detail by Simon in 1842 and has since then been the subject of study. It is a mite of the Demodicidae family, often called “follicle mite” because it lives inside the hair follicles of their hosts. It is vermiform, has four pairs of stubby legs and a striatum abdomen, lives in the sebaceous glands of the head, hair follicles of the face, eyelashes and meibomian glands of the eyelids, but can also be found in the chest, armpits and pubic region. Although found in asymptomatic individuals, their presence has been linked with various ophthalmological diseases such as conjunctivitis, chronic eczematous blefaritis, chalazia and contact lens intolerance. Its incidence in men increases with age.
The prior art reveals some treatments against Demodex Spp. Essential oils are more or less volatile substances, characterized by a strong odor and can contain about 20 to 60 components in very different concentrations, produced either by steam distillation or dry distillation or by a mechanical treatment of one species. These derived volatile compounds are mainly terpenes and their oxygenated derivatives, cyclic hydrocarbons, alcohols and aldehydes. Among the most important methods of obtaining essential oils in the prior art are the steam stripping; cold press extraction; solvent extraction by supercritical fluid extraction; hydrodistillation extraction assisted by microwave radiation; and effecting pretreatment with ultra low frequency sound.
An example of the use of essential oils having acaricidal effects, is one derived from the tea tree, such as disclosed in United States published patent application No. US 2012/0004320, to Gao, Yingying and others, and relating to a method for treating ocular disorders caused by the mite Demodex, such as blepharitis, Demodex induced rosacea, acne, etc., which method comprises administering to the patient a composition comprising a therapeutically effective amount of an oil chosen from a isoprenoidal essential oil substance such as tea tree oil; Terpinen-4-ol; carvone; alpha-terpineol; Cardinene; d-carvone; 1-carvone; gamma-terpinene; alpha-terpinene; 1, 8 cineole; alpha-terpineol; para-Cimene; alpha pinene; Limonene; (R)-(+)-Limonene; alpha-Thugene; eucalyptol; (+)-Ledene; Cuminic aldehyde; and Myrcene; where the administration comprises contacting the affected area of the lid margin and the tabs of the patient with the composition. However, it has been found that this composition based on tea tree is not completely effective because it does not act on the deformation of the animal body therefore its removal is not guaranteed.
All developments by Gao, are directed to treatment by using tea tree oils and therefore its consequent elimination is not fully guaranteed. For example patent applications in the US, such as US20090061025 to Gao et al discloses compositions containing about 0.6% to 20% tea tree oil in the form of solutions, suspensions, aerosols, lotions, gels, pastes, impregnated wipes, impregnated tissue, impregnated non-woven substrates, balms medicinal, cleaning products (including shampoos and soaps), creams or ointments. According to Gao et al, their invention is directed to compositions and methods for use in treating ocular infestations caused by Demodex Spp and related diseases using such compositions. According to US patent application US20130344128 also to Gao et al, a method is disclosed for treating an eye disorder such as blepharitis induced by the mite Demodex Spp, also treating rosacea, acne and dysfunction of the meibomian glands in a patient in need thereof, which method comprises administering to the patient a composition comprising a therapeutically effective amount of an essential oil chosen from the tea tree.
Gao also discloses the miticidal effect that occurs only at certain concentrations, but also illustrates the adverse irritation effects that occur in humans ranging from burns to tissue necrosis. Indeed, according to the studies reported by Gao, Yingying and others such as the background patents discussed above and in the publication entitled “In vitro and in vivo killing of ocular Demodex by tea tree oil (Destruction in vitro and in vivo of Demodex in the eye using tea tree oil), Extended Report Br. J. Ophthalmol 2005; 89: 1468-1473 doi: 10.1136/bjo Jun. 6, 2005; defined concentrations that generated varying degrees of irritation in some patients.
Another example of prior art is Patent Application US20040156873 to Gupta et al disclosing compositions for treating acne and rosacea with a treatment strategy using a synergistic combination for controlling the production of excess sebum; control of undesirable bacteria or mites; control inflammation; increasing the peeling of follicular infundibulum cells; reducing anti-acne rosacea or irritation; and improved bioavailability of the topical anti-acne and rosacea compositions. This is achieved by a synergistic combination of anti-acne and rosacea topical ingredients, commonly used with a topical composition having improved bioavailability, which results in increased action of anti-acne and rosacea treatment based on the ingredients. Moreover, this prior also discloses the additional inclusion of an anti-inflammatory composition and a composition for improving vascular microcirculation.
U.S. Pat. No. 7,575,764 to Chen et al discloses topical compositions comprising Hypsizygus ulmarius extract in amounts that are effective to influence polymorphonuclear leukocytes mediated chemotaxis. Hypsizygus ulmarius extract may be used alone or in combination with anti-inflammatory active agents and secondary skin agents, such as other fungi and/or natural extracts. Secondary anti-inflammatory agents may or may not function by antagonizing mediated chemotaxis. According to that patent, the extract can be incorporated into a cosmetically acceptable carrier.
PCT WO0151014 to Eini et al discloses a composition for topical application characterized by rheological properties comprising by weight, 1 to 25% of a solidifying agent and 75-99% of a hydrophobic solvent, wherein the solidifying agent is selected the group consisting of a fatty long chain alcohol having at least 15 carbon atoms in its carbon backbone and a fatty acid having at least 18 carbon atoms in its carbon backbone and wherein said solidification agent includes a substance selected so that under ambient conditions, the carrier is semi-solid at rest and liquefies with the application of shearing thereto and wherein said hydrophobic solvent is selected from the group consisting of at least an oil derived from a marine animal or terrestrial or a mineral oil and at least one vegetable oil.
US application No. 20130053353 to Tamarkin et al, illustrates a substantially surfactant free composition for cosmetic or pharmaceutical application comprising: a) a first rheology modulator comprising a suspended pharmaceutical active agent or a suspended cosmetic active agent; b) a second rheology modulator selected from the group consisting of: at least one fatty alcohol, at least one fatty acid, at least one wax, and mixtures of two or more thereof; and c) a hydrophobic carrier comprising at least one hydrophobic solvent; wherein the composition comprises less than about 0.1% by weight surfactant; wherein the composition comprises less than about 2% by weight water; wherein the viscosity of the composition is at least about 30% higher than the viscosity of a first partial composition comprising the second rheology modulator agent and the hydrophobic carrier without the first rheology modulator; and is higher than the viscosity of a second partial composition comprising the first rheology modulator and the hydrophobic carrier without the second rheology modulator; and wherein the viscosity of the first partial composition is less than about 25,000 cPs at room temperature.
Therefore, there is a long term need for a composition with regard to the form of administration which include therapeutic application easily without causing toxicity, rapid acaricide action and effective action not only in the mite itself but eggs that have been deposited, resulting in greater action in clinical treatment.
So, an important aspect of the instant invention is that the acaricide action does not cause severe and adverse effects in humans and in turn, dehydrate and destroy the mites and their eggs by the lipolytic effect that solubilizes the lipid membranes of the anatomical structure the mites.